Pain is defined as an unpleasant sensory and emotional experience. Pain, however, can be informative and useful. For example, nociceptive pain is often indicative of injury (e.g., tissue damage), and such pain typically evokes escape or protective behaviors in animals, including humans. However, inflammation, cellular and neuronal damage and other processes resulting from injury or disease can lead to states of chronic pathological pain. Hyperalgesia is a condition in which enhanced sensitivity to noxious stimuli is present, and thus the perception of pain is exaggerated. Allodynia is a condition in which normally non-noxious stimuli become painful. Persistent or chronic pain, manifested as hyperalgesia and/or allodynia, remains challenging to treat. Many patients do not respond to existing therapeutics, or have their pain poorly managed (i.e., inadequate relief), or experience relief of an inadequate duration.
Chronic pain contributes to over $600 billion worth of healthcare expenditures annually, more than the yearly cost of cancer, heart disease, and diabetes combined. Neuropathic pain affects between 6 and 10% of the population, and is associated with decreased quality of life and socioeconomic burdens exceeding all other chronic pain disorders. A recent meta-analysis of more than 200 neuropathic pain clinical trials indicates that the number of drugs needed to achieve even 50% pain relief in this population is between 4 and 10. This lack of efficacy has a profound influence on patient quality of life and is a source of frustration for caregivers. Many existing neuropathic pain therapeutics either have unknown mechanisms or are thought to reduce pain by reducing neuronal excitability.
Administration of opioids to treat pain is a well-recognized and commonly employed therapy in medicine. Mu opioids from natural sources have used by humans for millennia for a wide variety of purposes, including the relief of dysentery and pain. Opium alkaloids were not isolated until the 1800s, and synthetic opioids, whether recapitulations of nature or newly designed molecules, came much later. Mu opioid agonists are considered gold standard analgesic agents, and are widely used for the treatment of a variety of mostly moderate-to-severe pain conditions in humans.
However, tachyphylaxis, tolerance to opioids and opioid-induced hyperalgesia can often result during the course of therapy. In such patients, increasingly higher doses of opioids are needed to provide an acceptable level of pain relief and, in doing so, the patient is thereby subjected to a higher risk of adverse side effects and safety concerns, which include respiratory depression, constipation, nausea and vomiting. Prolonged opioid therapy to treat chronic pain states may subject the patient to develop dependence on opioids, suffer opioid withdrawal on discontinuation of treatment, and some patients may be more susceptible to engage in abuse of these medications. These phenomena present significant clinical challenges for pain treatment.
G-Protein coupled receptors are membrane-bound proteins that contain seven transmembrane domains, an extracellular N-terminus, intracellular loops and an intracellular C-terminus. The GPCR family constitutes the largest class of cell surface receptors in the human genome (˜800 different members), and small molecules that modulate GPCRs account for nearly one third of all marketed drugs.
Historically, from a conceptual perspective, GPCRs were thought to behave as switches (off/on), whereupon agonist binding induces a single conformational change to recruit G-protein coupling, thereby producing second-messengers such as cAMP to alter cellular functions (e.g., polarization (neurons), contractility (myocytes), transcription, translation, and so forth). Antagonists block agonist access, thereby providing a means to prevent GPCR activation, which is also useful therapeutically depending upon the specific GPCR.
Upon ligand binding, GPCRs can not only interact with G-proteins as described above, but may also recruit cytosolic proteins of the arrestin family. Arrestin recruitment often occurs as a result of phosphorylation by a family of G-protein receptor kinases (GRKs). One role of the β-arrestin pathway, in contrast to G-protein binding, is to turn off signaling, possibly serving as an evolutionary ‘brake’ to avoid deleterious effects of constitutive signaling. β-Arrestins accomplish signal termination in several ways: 1) G-protein uncoupling causes desensitization (loss of signaling); 2) degradation of the second messenger(s) turns down/off signaling; and 3) receptor internalization precludes agonist binding and signaling since the receptor is not exposed/present on the cell membrane. Furthermore, there are non-classical signaling modalities (e.g., MAP kinase) that can be activated by β-arrestins.
There is a thus a need in the art for novel compounds and/or compositions that can be used to treat pain and/or reduce hyperalgesia and allodynia. In certain embodiments, the compounds and/or compositions do not induce significant (or any at all) respiratory depression, constipation, and/or tolerance. The present invention addresses this unmet need.